Inflammation disorders, such as arthritis, colitis, and autoimmune diabetes, typically manifest themselves as disorders distinct form those associated with reperfusion injury, e.g., stroke and heart attack, and can clinically manifest themselves as different entities. However, there can be common underlying mechanisms between these two types of disorders. In particular, inflammation and reperfusion injury can induce proinflammatory cytokine and chemokine synthesis. Induction of pro-inflammatory cytokines can, in turn, result in production of cytotoxic free radicals such as nitric oxide and superoxide. NO and superoxide can react to form peroxynitrite (ONOOxe2x88x92) (Szabxc3x3 et al., Shock 6:79-88, 1996).
The peroxynitrite-induced cell necrosis observed in inflammation and reperfusion injury involves, in significant part, the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Activation of PARS is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion injury (Szabxc3x3 et al., Trends Pharmacol. Sci. 19: 287-98, 1998).
The invention is based in part on the discovery of novel substituted 6(5H)phenanthridinone derivatives and their unexpected effects in inhibiting inflammation, in treating reperfusion injuries, and in reducing the severity of diabetes.
Accordingly, in one aspect the invention provides novel substituted 6(5H)phenanthridinone derivatives falling within formula I, as set forth in the Detailed Description of the Invention, below.
Also provided is a method of treating inflammatory and reperfusion conditions in mammals by administering to a mammal in need of such treatment an effective amount of a compound according to formula I.
In a further aspect, the invention also includes a method for the production of compounds of formula I.
The substituted 6(5H)phenanthridinone compounds of the invention are potent, pharmaceutical compounds that can be used to treat a variety of conditions and diseases, typically those known to involve inflammatory mediator production and cell death.
The details of one or more embodiments of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated by reference.